Summary: D-Cycloserine reduces neuropathic pain behavior
through limbic NMDA-mediated circuitry q
Magali Millecamps, Maria V. Centeno, Hector H. Berra, Charles N. Rudick,
Simona Lavarello, Tatiana Tkatch, A. Vania Apkarian *
Department of Physiology, Feinberg School of Medicine, Northwestern University, 303 E Chicago Ave., Chicago, IL 60611, United States
Received 7 August 2006; received in revised form 20 February 2007; accepted 5 March 2007
Abstract
Human brain imaging studies suggest that chronic neuropathic pain has a strong emotional component that is mediated by med-
ial prefrontal cortex (mPFC) activity; in rodents, the mPFC is involved in emotional and cognitive aspects of behavior, including the
extinction of Pavlovian fear conditioning. Together, these findings suggest that the cortex may modulate the memory trace of pain.
As D-cycloserine (DCS), a partial agonist of the NMDA receptor, can enhance learning and potentiate the extinction of acquired
fear, in the present study we tested its efficacy in neuropathic pain behavior. In rats with spared nerve injury (SNI), repeated daily
oral administration of DCS reduced mechanical sensitivity of the injured limb in a dose-dependent manner; this effect continued for
weeks after the cessation of DCS treatment. In addition, re-exposure to DCS further enhanced antinociceptive behavior. Repeated
oral DCS administration also reduced cancer chemotherapy drug-induced neuropathic pain behavior. Infusions of DCS directly into
the mPFC (especially within prelimbic cortex) or the amygdala (but not into thalamus, insula, or occipital cortex) acutely induced
antinociception in SNI rats. The antinociceptive effect of intra-mPFC DCS infusions was mimicked by NMDA and glycine, and
blocked by HA 966. In the mPFC of SNI rats, NR2B expression was down-regulated; however, this effect was reversed with
repeated oral DCS. Lastly, infusions of DCS into mPFC reversed place avoidance behavior induced by mechanical stimulation
of the injured paw in SNI rats. These findings indicate that limbic NMDA-mediated circuitry is involved in long-term reduction